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Cell Rep. 2016 Dec 13;17(11):3035-3048. doi: 10.1016/j.celrep.2016.11.058.

Cumulative Impact of Polychlorinated Biphenyl and Large Chromosomal Duplications on DNA Methylation, Chromatin, and Expression of Autism Candidate Genes.

Author information

1
Medical Microbiology and Immunology, UC Davis, Davis, CA 95616, USA; Genome Center, UC Davis, Davis, CA 95616, USA; MIND Institute, UC Davis, Davis, CA 95616, USA; Center for Children's Environmental Health, UC Davis, Davis, CA 95616, USA.
2
Center for Children's Environmental Health, UC Davis, Davis, CA 95616, USA; Veterinary Molecular Biosciences, UC Davis, Davis, CA 95616, USA.
3
Genome Center, UC Davis, Davis, CA 95616, USA.
4
Advanced Science Research Center, Kanazawa University, 13-1 Takaramachi, Kanazawa 920-8640, Japan.
5
Medical Microbiology and Immunology, UC Davis, Davis, CA 95616, USA; Genome Center, UC Davis, Davis, CA 95616, USA; MIND Institute, UC Davis, Davis, CA 95616, USA; Center for Children's Environmental Health, UC Davis, Davis, CA 95616, USA. Electronic address: jmlasalle@ucdavis.edu.

Abstract

Rare variants enriched for functions in chromatin regulation and neuronal synapses have been linked to autism. How chromatin and DNA methylation interact with environmental exposures at synaptic genes in autism etiologies is currently unclear. Using whole-genome bisulfite sequencing in brain tissue and a neuronal cell culture model carrying a 15q11.2-q13.3 maternal duplication, we find that significant global DNA hypomethylation is enriched over autism candidate genes and affects gene expression. The cumulative effect of multiple chromosomal duplications and exposure to the pervasive persistent organic pollutant PCB 95 altered methylation of more than 1,000 genes. Hypomethylated genes were enriched for H2A.Z, increased maternal UBE3A in Dup15q corresponded to reduced levels of RING1B, and bivalently modified H2A.Z was altered by PCB 95 and duplication. These results demonstrate the compounding effects of genetic and environmental insults on the neuronal methylome that converge upon dysregulation of chromatin and synaptic genes.

KEYWORDS:

DNA methylation; autism; chromatin; copy number variants; epigenetic; gene x environment interaction; persistent organic pollutants

PMID:
27974215
PMCID:
PMC5206988
DOI:
10.1016/j.celrep.2016.11.058
[Indexed for MEDLINE]
Free PMC Article

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